Fatigue is recognized as one of the most disabling and frequent symptoms of multiple sclerosis (MS). Amantadine appears to have some proven ability to alleviate the fatigue in MS. The aim of this study was to assess the efficacy of co-administration of amantadine and aspirin for the treatment of fatigue in multiple sclerosis. Forty-five ambulatory patients aged 20–50 years with a diagnosis of MS, a stable disability level ?6 on the Kurtzke extended disability status scale (EDSS), and a mean score ?4 on the fatigue severity scale (FSS) were eligible for the 6 weeks, randomized placebo-controlled double-blind study . Patients were randomly assigned to receive either amantadine hydrochloride (100-mg) and aspirin (500 mg) or amantadine hydrochloride (100 mg) and matching placebo twice daily throughout 6 weeks. Efficacy was evaluated by self rating scales, using the FSS. Data analysis was performed by T test, chi-square test, Wilcoxon and ANOVA tests. Mean FSS for the amantadine+aspirin group was 3.5 6 ±0.5 and mean FSS for amantadine + placebo group was 4.1 6 ±0.5 at day 30. Mean FSS for the amantadine + aspirin group was 3.3 6 ± 0.5 and mean FSS for amantadine + placebo group was 3.9 6 ± 0.5 at day 42. Amantadine and aspirin treated patients showed a significantly greater reduction in fatigue, as measured by the FSS, than those patients were treated with amantadine and placebo (p <0.001). Our findings demonstrate that co-administration of amantadine and aspirin was significantly better than amantadine and placebo in treating fatigue in MS patients.